The combination of hydroxycitrate (HCA) and carnitine has been recommended as a diet aid based on its presumed ability to promote the transport of free fatty acids (FFAs) into hepatic mitochondria, a major site of fatty acid oxidation (McCarty, M., Med. Hypoth. 42:215-225, 1994; McCarty, M., Med. Hypoth. 45:247-254, 1995). This transport step is believed to be rate-limiting for hepatic ketogenesis (McGarry et al., Proc. Natl. Acad. Sci. U.S.A. 72:4385-4388, 1975; McGarry et al., Annu. Rev. Biochem. 49:395-420, 1980).
More specifically, the conversion of cytoplasmic fatty acyl coA to fatty acyl carnitine via the enzyme carnitine palmitoyl transferase I (CPT) is pace-setting for fatty acid transport into mitochondria and thus for ketogenesis in which fatty acids are oxidized (McGarry et al., supra.). HCA, the main acid found in fruits of the genus Garcinia, disinhibits CPT by suppressing synthesis of malonyl coA, a key allosteric inhibitor of this enzyme. Carnitine is the essential cofactor for CPT activity, and ordinary non-fasting hepatocyte levels of this enzyme appear to be subsaturating, such that provision of extra carnitine accelerates hepatic ketogenesis when CPT is activated.
Although the process of ketogenesis reduces both nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD), ketogenesis can proceed at a high rate even when hepatocyte metabolism is generating ADP at a low rate. Berry et al. (Eur. J. Biochem., 131:205-214, 1983) suggest that during ketogenesis, high energy electrons enter the respiratory chain at a greater rate than hepatocytes can generate ADP, resulting in an electron glut and an increased electrochemical proton gradient. Under these circumstances, electrons entering the chain at the level of coenzyme Q (CoQ) (via the FAD-dependent acyl coA dehydrogenase reaction) can be "pushed" up the respiratory chain to AND dehydrogenase which transfers them to NAD+. These electrons can then be transported to the cytosol via the malate/aspartate shuttle and, after reducing NAD+ or NAD(P) in the cytosol, can then re-enter the mitochondrial respiratory chain at the CoQ level via the glycerol-3-phosphate shuttle. The "reverse electron transport" step in this cycle is driven by the electrochemical proton gradient of the mitochondrial inner membrane--which diminishes as a result--or, alternatively, by the conversion of ATP to ADP via the mitochondrial ATP synthase. After two "turns" of this cycle, the electrochemical proton gradient will be sufficiently diminished to enable the electrons to pass down the respiratory chain from CoQ to oxygen, without any coupling to ATP synthesis. Alternatively, the two ADP generated by two turns of the cycle will enable the coupled transport of these electrons from CoQ to oxygen. This mechanism would effectively "uncouple" the transfer of electrons from FADH.sub.2 to oxygen during ketogenesis, thus resulting in continuous fatty acid oxidation and consequent fat loss.
Pyruvate has also been shown to exert a fat loss-promoting effect (Stanko et al., Metabolism 35:182-186, 1986; Stanko et al., J. Animal Sci. 67:1272-1278, 1989; Cortez et al., Am. J. Clin. Nutr. 53:847-853, 1991; Stanko et al., Am. J. Clin. Nutr. 55:771-776, 1992; Stanko et al., Am. J. Clin. Nutr. 56:630-635, 1992; Stanko et al., Int. J. Obesity 20:925-930, 1996).
There is a constant need for methods of promoting weight and fat loss. The present invention provides such a method.